High occurrence of CRLF2 abnormalities in Mexican children with B-cell acute lymphoblastic leukemia

Juárez-Velázquez, Rocío; Moreno-Lorenzana, Dafné Linda; Anaya, Daniel Alejandro Martínez; Monterde, Eduardo Adrián Hernández; Aguilar-Hernández, María Montserrat; Reyes-León, Adriana; Chávez-González, María Antonieta; Santiago, Norma López; Tarres, Marta Zapata; Villegas, Luis Juárez; Sánchez, Netzi Rivera; Lerma, Oscar Soto; Vega-Vega, Lourdes; Luna, Roberto Rivera; Pérez-Vera, Patricia

doi:10.1016/j.cyto.2022.155896

Cited by 7 publications

(5 citation statements)

References 35 publications

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“…Raca et al 2017 determined that IGH::CRLF2 is the most common rearrangement in Hispano–Latino ALL children from Los Angeles [ 20 ]. Similar results were obtained by our group as we observed that CRLF2 overexpression and rearrangements are frequent in Mexican pre-B ALL children [ 22 ]. In the present study, the strategy to detect Ph-like patients was suitable to identify CRLF2 abnormalities; in most of the cases, it was possible to associate the CRLF2 overexpression with a rearrangement, point mutation, and/or an extra copy of the gene ( Figure 1 ).…”

Section: Discussionsupporting

confidence: 91%

“…Despite this study not being designed to obtain the frequency of the Ph-like subtype in our population, due to the high incidence of CRLF2 abnormalities found, we can suggest that this subset is well represented in Mexican pre-B ALL patients. However, rearrangements of CRLF2 can also be found in non-Ph-like patients [ 22 ] and, thus, this may affect the true frequency of Ph-like patients in this study.…”

Section: Discussionmentioning

confidence: 95%

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Characterization of Philadelphia-like Pre-B Acute Lymphoblastic Leukemia: Experiences in Mexican Pediatric Patients

Martìnez-Anaya

Moreno‐Lorenzana

Reyes-León

et al. 2022

IJMS

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Ph-like subtypes with CRLF2 abnormalities are frequent among Hispano–Latino children with pre-B ALL. Therefore, there is solid ground to suggest that this subtype is frequent in Mexican patients. The genomic complexity of Ph-like subtype constitutes a challenge for diagnosis, as it requires diverse genomic methodologies that are not widely available in diagnostic centers in Mexico. Here, we propose a diagnostic strategy for Ph-like ALL in accordance with our local capacity. Pre-B ALL patients without recurrent gene fusions (104) were classified using a gene-expression profile based on Ph-like signature genes analyzed by qRT-PCR. The expressions of the CRLF2 transcript and protein were determined by qRT-PCR and flow cytometry. The P2RY8::CRLF2, IGH::CRLF2, ABL1/2 rearrangements, and Ik6 isoform were screened using RT-PCR and FISH. Surrogate markers of Jak2-Stat5/Abl/Ras pathways were analyzed by phosphoflow. Mutations in relevant kinases/transcription factors genes in Ph-like were assessed by target-specific NGS. A total of 40 patients (38.5%) were classified as Ph-like; of these, 36 had abnormalities associated with Jak2-Stat5 and 4 had Abl. The rearrangements IGH::CRLF2,P2RY8::CRLF2, and iAMP21 were particularly frequent. We propose a strategy for the detection of Ph-like patients, by analyzing the overexpression/genetic lesions of CRLF2, the Abl phosphorylation of surrogate markers confirmed by gene rearrangements, and Sanger sequencing.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 95%

Characterization of Philadelphia-like Pre-B Acute Lymphoblastic Leukemia: Experiences in Mexican Pediatric Patients

Martìnez-Anaya

Moreno‐Lorenzana

Reyes-León

et al. 2022

IJMS

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“…The most relevant differences in Mexican patients are: the lower incidence of t ( 12 , 21 )( ETV6::RUNX1 ), similar to Hispanics ( 22 , 26 ). The t ( 1 , 19 )( TCF3::PBX1 ) is slightly more frequent in Mexicans than in Hispanics and non-Hispanics ( 22 , 27 ); abnormalities in CRLF2 are particularly frequent in Mexicans, with a similar incidence of IGH::CRLF2 compared to Hispanics, and P2RY8::CRLF2 is present with a higher frequency, all patients with these rearrangements presented CRLF2 overexpression ( 28 – 30 ); the iAMP21 is also frequent (10.1% in B-Others) ( 26 , 29 ). This means that in Mexicans, ETV6-RUNX1 , associated with standard prognosis, is reduced, and rearrangements of CRLF2 and iAMP21 , which confer high risk, are widely represented among Mexican patients.…”

Section: Epidemiological Considerations In Pediatric Allmentioning

confidence: 98%

Triple-hit explanation for the worse prognosis of pediatric acute lymphoblastic leukemia among Mexican and Hispanic children

Rivera-Luna

Pérez-Vera

Galvan-Diaz³

et al. 2022

Front. Oncol.

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Acute lymphoblastic leukemia (ALL) is the most common malignancy among Mexican and Hispanic children and the first cause of death by disease in Mexico. We propose a “triple-hit” explanation for the survival gap affecting this population. The first hit can be attributed to epidemiology and social, cultural, and economic burdens. The second hit refers to cancer biology, with a high incidence of unfavorable genetic characteristics associated with an unfavorable response to treatment and, subsequently, poor survival. Finally, the third hit relates to sub-optimal treatment and support. Society and culture, leukemia biology, and treatment approach limitations are key factors that should not be seen apart and must be considered comprehensively in any strategy to improve the prognosis of Mexican and Hispanic children with ALL.

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“…Conversely, diminished CRLF2 expression due to deletion of colony-stimulating factor 2 receptor alpha (CSF2RA) leads to the gene being controlled by CSF2RA, a low-affinity enhancer [66,67]. The Phe232Cys substitution mutation in the extracellular domain of CRLF2 enhances its function, leading to constitutive homodimerization of CRLF2 and activating components of the JAK-STAT pathway [61,65,70].…”

Section: Enhancement Of Crlf2 Functionmentioning

confidence: 99%

“…CRLF2 overexpression resulting from the described genetic abnormalities is detected in 15% of children with high-risk B-ALL and 47% of pediatric patients with Ph-like B-ALL [55,71]. Therefore, high expression is considered one of the characteristic features of this subtype of ALL and, according to some researchers, has the potential to be a prognostic factor when making decisions regarding treatment selection [70,72]. There is a correlation between impaired gene expression and the ethnic origin of patients.…”

Section: Clinical Significance Of Crlf2 Mutationsmentioning

confidence: 99%

The Role of the JAK–STAT Pathway in Childhood B-Cell Acute Lymphoblastic Leukemia

Ziętara,

Wróblewska,

Zajączkowska

et al. 2024

IJMS

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B-cell lymphoblastic leukemia is a hematologic neoplasm that poses a serious health concern in childhood. Genetic aberrations, such as mutations in the genes IL-7, IL7R, JAK1, JAK2, TLSP, CRLF2, and KTM2A or gene fusions involving BCR::ABL1, ETV6::RUNX1, and PAX5::JAK2, often correlate with the onset of this disease. These aberrations can lead to malfunction of the JAK–STAT signaling pathway, which is implicated in various important biological processes, including those related to immunology. Understanding the mechanisms underlying the malfunction of the JAK–STAT pathway holds potential for research on drugs targeting its components. Available drugs that interfere with the JAK–STAT pathway include fludarabine, ruxolitinib, and fedratinib.

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High occurrence of CRLF2 abnormalities in Mexican children with B-cell acute lymphoblastic leukemia

Cited by 7 publications

References 35 publications

Characterization of Philadelphia-like Pre-B Acute Lymphoblastic Leukemia: Experiences in Mexican Pediatric Patients

Characterization of Philadelphia-like Pre-B Acute Lymphoblastic Leukemia: Experiences in Mexican Pediatric Patients

Triple-hit explanation for the worse prognosis of pediatric acute lymphoblastic leukemia among Mexican and Hispanic children

The Role of the JAK–STAT Pathway in Childhood B-Cell Acute Lymphoblastic Leukemia

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